Project Summary Of the two main goals of the HIV-1 field ? immune protection of the uninfected, and cure ? cure is more imaginable at present. Certainly a globally applicable sterilizing vaccine seems far away. There is little optimism that currently available strategies will produce effective adaptive immune system protection against HIV-1 for uninfected but at-risk individuals (people with the disease of addiction, people with sexual exposure). This NIDA Avant Garde project will align with RFA goals by pursuing a solidly innovative direction that also differs strongly from our previous work. It concerns innate rather than adaptive immunity, and it is based on our recently published body of data showing that transgenic expression of a viral RNA-dependent RNA polymerase (RdRP), in the absence of other viral proteins, and therefore unsequestered in the cell within viral replication factories, can profoundly reconfigure mammalian innate antiviral immunity. It dramatically upregulates many antiviral factors, and provides broad-spectrum antiviral protection to mice. This response is strongly HIV-1-protective in corroborative human cell models. We hypothesize that it may also have application to the co-infection pathogens that afflict people with addiction. In the mouse, the radically altered innate immune system proteome is stable life-long and, surprisingly, does not trigger any inflammatory pathology. Along with the profound antiviral effects, this latter provocative and counterintuitive observation has multiple downstream discovery opportunities. Here we will determine the mechanisms involved and use the discoveries to formulate new strategies to achieve protection against HIV-1 in at-risk populations.